Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa after Elexacaftor-Tezacaftor-Ivacaftor in Cystic Fibrosis

Abstract

Rationale: Evaluating approaches to reduce treatment burden is a research priority among people with cystic fibrosis on highly effective modulators, including elexacaftor-tezacaftor-ivacaftor (ETI). Objectives: We sought to evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods: SIMPLIFY participants ≥12 years old on ETI and constituting a subgroup using both HS and DA at study entry were randomized to the HS or DA trial and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run-in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY and a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth, and percent predicted forced expiratory volume in 1 second (ppFEV₁) at study entry. Results: Forty-three participants discontinued both therapies by the end of SIMPLIFY, and 63 remained on both, with overall average ppFEV₁ of 96.7% at study entry and 3.9 months as the average duration of follow-up from beginning of the first trial to completion of the second trial, including time between trials. No clinically meaningful difference in the change in ppFEV₁ from baseline to completion of the second trial was observed between those who discontinued and those who remained on both therapies (difference: 0.22% off-on; 95% confidence interval = -1.60, 2.03). Changes in lung clearance index at 2.5% starting concentration, patient-reported outcomes, and safety outcomes were also comparable. Patient-reported treatment burden, as measured by a Cystic Fibrosis Questionnaire-Revised subscale, significantly decreased in those who discontinued both therapies. Conclusions: SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared with those who remained on both therapies. These data continue to inform a new era of postmodulator care of people with cystic fibrosis.

Keywords: CFTR modulators; treatment burden; treatment discontinuation.

Figure 1.

Overview of analysis cohorts among those in the SIMPLIFY study who were eligible to enroll in both trials. DA = dornase alfa; HS = hypertonic saline.

Figure 2.

Frequency distribution of the time between the end of Trial 1 and beginning of the 2-week run-in period for Trial 2 among all participants enrolling in both trials. The majority of participants immediately enrolled in the second trial after participating in the first trial. Analyses adjusted for time between trials, with no significant effects of the time between trials on treatment effect estimates.

Figure 3.

Changes in (A) percent predicted forced expiratory volume in 1 second (ppFEV₁), (B) Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain scores (higher scores reflect less symptoms), (C) CFQ-R treatment burden domain scores (higher scores reflect less burden), and (D) Chronic Respiratory Infection Symptom score (CRISS) (lower scores reflect less symptoms) over the SIMPLIFY study from baseline of the first trial to completion of the second 6-week randomized trial. Error bars represent 95% confidence intervals (CIs). Time between the end of Trial 1 and the beginning of Trial 2 was variable and is represented by a dotted line.

Figure 4.

Changes in lung clearance index at 2.5% starting concentration (LCI_2.5) over the SIMPLIFY study from baseline of the first trial to completion of the second 6-week randomized trial. Error bars represent 95% confidence intervals (CIs). Time between the end of Trial 1 and the beginning of Trial 2 was variable and is represented by a dotted line.